Dr Uppaluri on the Implications of the FDA Approval of Perioperative Pembrolizumab in Resectable, Locally Advanced HNSCC

“The significance of this [approval] is huge for patients in the field because the first time in over 20 years, there's been a change in the current paradigm for these patients [with resectable, locally advanced head and neck squamous cell carcinoma.”

Ravindra Uppaluri, MD, PhD, director of Head and Neck Surgical Oncology at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, discussed the recent FDA approval of pembrolizumab (Keytruda) for use in the neoadjuvant and adjuvant setting for patients with resectable, locally advanced head and neck squamous cell carcinoma (HNSCC).

On June 12, 2025, the FDA approved pembrolizumab as a single agent as neoadjuvant treatment, continued as adjuvant treatment in combination with radiotherapy with or without cisplatin after surgery, and then as a single agent, for adult patients with resectable, locally advanced HNSCC whose tumors express PD-L1 with a combined positive score (CPS) of at least 1, as determined by an FDA-approved test.

This regulatory decision, supported by data from the phase 3 KEYNOTE-689 trial (NCT03765918), represents the first major shift in the standard treatment paradigm for this population in over two decades, Uppaluri said.

Findings from KEYNOTE-689 supporting the approval demonstrated that the addition of pembrolizumab to standard therapy in patients with PD-L1 CPS of 1 or higher significantly improved event-free survival (EFS) compared with standard therapy alone (HR, 0.70; 95% CI, 0.55-0.89; P = .0014). The median EFS was 59.7 months (95% CI, 37.9-not reached) in the pembrolizumab arm vs 29.6 months (95% CI, 19.5-41.9) in the control arm.

Traditionally, the management of resectable stage III to IV HNSCC has involved definitive surgery followed by adjuvant radiotherapy, with or without concurrent chemotherapy, Uppaluri said. This approach has been the standard of care over the past 20 years, Uppaluri noted.

According to Uppaluri, this approval signifies an important evolution in the management of locally advanced HNSCC, offering a new treatment strategy for patients who historically had limited therapeutic options beyond surgery and radiation.